Genetic causes of male infertility: snapshot on morphological abnormalities of the sperm flagellum

Jean-Fabrice Nsota Mbango,Charles Coutton,Christophe Arnoult,Pierre F. Ray,Aminata Touré

doi:10.1186/s12610-019-0083-9

Abstract

Male infertility due to Multiple Morphological Abnormalities of the sperm Flagella (MMAF), is characterized by nearly total asthenozoospermia due to the presence of a mosaic of sperm flagellar anomalies, which corresponds to short, angulated, absent flagella and flagella of irregular calibre. In the last four years, 7 novel genes whose mutations account for 45% of a cohort of 78 MMAF individuals were identified: DNAH1, CFAP43, CFAP44, CFAP69, FSIP2, WDR66 (CFAP251), AK7. This successful outcome results from the efficient combination of high-throughput sequencing technologies together with robust and complementary approaches for functional validation, in vitro, and in vivo using the mouse and unicellular model organisms such as the flagellated parasite T. brucei. Importantly, these genes are distinct from genes responsible for Primary Ciliary Dyskinesia (PCD), an autosomal recessive disease associated with both respiratory cilia and sperm flagellum defects, and their mutations therefore exclusively lead to male infertility. In the future, these genetic findings will definitely improve the diagnosis efficiency of male infertility and might provide genotype-phenotype correlations, which could be helpful for the prognosis of intracytoplasmic sperm injection (ICSI) performed with sperm from MMAF patients. In addition, functional study of these novel genes should improve our knowledge about the protein networks and molecular mechanisms involved in mammalian sperm flagellum structure and beating.

Highlights

In the last decade, tremendous work was performed in the field of reproductive biology in order to identify genetic causes of male infertility
Morphological Abnormalities of the sperm Flagella (MMAF) is characterized by nearly total asthenozoospermia due to the presence of a mosaic of sperm flagellar anomalies which corresponds to short, angulated, absent flagella and flagella of irregular calibre (Fig. 1)
An additional level of complexity results from the type of mutation, which may differently impact cilia and sperm cells and cause different phenotypes in those organelles. This point is documented with AK7 gene, which loss of function in the mouse induces a Primary Ciliary Dyskinesia (PCD) phenotype with male infertility and MMAF phenotype [27, 33], while a missense mutation identified in two MMAF brothers, induces the absence of AK7 protein and axonemal defects in the sperm but no protein damage, nor cilia structure and function in respiratory cells from the patient [27]

Summary

Introduction

Tremendous work was performed in the field of reproductive biology in order to identify genetic causes of male infertility. Akap4 gene invalidation in the mouse was shown to induce a MMAF-like phenotype [11], this genomic deletion was identified in a single MMAF infertile man and limited analysis was performed to confirm the pathogenicity of the mutation; this result needs to be confirmed in other patients.

Results

Conclusion